Fenofibrate, a compound with the chemical name of isopropyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionate, lowers the levels of serum cholesterol, LDL-cholesterol, and triglyceride, and raises HDL-cholesterol levels. Fenofibrate has been appreciated, worldwide including in Japan, as an antihyperlipidemic agent which improves overall lipid metabolism.
Fenofibrate has been conventionally formulated as a hard capsule form (hereinafter, may be briefly referred to as “capsule”). Fenofibrate compositions with improved bioavailability have been studied. For example, Japanese Examined Patent Publication No. Hei 7-14876 (JP 7-14876, B (1995)) has disclosed the composition containing a homogeneous mixture of co-micronized particles (hereinafter, may be referred to as “co-micronizate”) of fenofibrate and a solid surfactant.
Generally, when a drug must be orally taken over a long period of time, first, the fewer number of capsule per dose as well as preparations of easily ingestable size greatly leads to improvement of patient's compliance with drug-taking. Such improvement of the drug-taking compliance becomes more important especially in the case of the elderly who experience hypofunction in swallowing.
For hyperlipemia, an indication to which the fenofibrate preparations are applied, in most cases, patients are required to take the drug over a long period of time such as a yearly basis, also a majority of the patients are elderly persons, and further there are lots of cases where several types of concomitant drugs are frequently prescribed due to complications with diabetes and arteriosclerosis. Under such circumstances, it has been strongly desired to develop minimized and easily ingestable preparations without increasing the number of capsule per dose.
In the case of the above prior art composition containing the co-micronizate of fenofibrate and the solid surfactant (hereinafter, referred to as “co-micronized composition”), it enables the improvement in bioavailability, leading to the reduction of 300 mg fenofibrate dosage per day to ⅔, 200 mg. However, even in the case of such co-micronized compositions, when formulated, pharmaceutical additives such as an excipient, a binder and a disintegrator (hereinafter, also simply referred to as additives) are required to be added. In the above prior art, the total amount of fenofibrate and the additives per capsule for the capsule preparation containing 200 mg of co-micronizate of fenofibrate becomes approximately 297 to 350 mg (the preparation examples I and II in Japanese Examined Patent Publication No. Hei 7-14876 (JP 7-14876, B (1995))). To fill up them in one capsule, there is no other choice than to use the size No. 1 capsule (major axis: approx. 19.1 mm and minor axis: 6.9 mm) or larger one.
Currently, capsules available for pharmaceutical use are supplied in 8 sizes, i.e., the hard capsules are numbered from the size No. 000 (the largest size with major axis: approx. 26.0 mm and minor axis: 10.0 mm) to the size No. 5 (the smallest size with major axis: 11.1 mm and minor axis: 4.9 mm) (see: for example, Otsuka, A. et al. (Ed.), “SEIZAIGAKU (4th Edition)”, p. 91, Nankodo Co. Ltd., Japan, 1990; Murata, T. et al. (Ed.), “YAKUZAIGAKU (revised 5th Edition)”, p. 130, Nankodo Co. Ltd., Japan, 1997). However, when the patients take the drug orally, the smaller the capsule size and the fewer number of the capsule per dose, the less the patient's burden, which leads improvement in patient's compliance. Thus, in many cases, the capsules equal to or smaller than size No. 2 (major axis: approx. 17.6 mm and minor axis: 6.4 mm) have been favorably used. However, although it became possible to make the co-micronized composition to reduce the amount of the active ingredient to ⅔, neither pharmaceutical formulation nor technology has been found that allows 200 mg of fenofibrate which is a dose per day to be filled into one capsule equal to or smaller than the size No. 2 capsule.